Maricel V. Maffini
Laura N. Vandenberg- 1Independent Consultant, Frederick, MD, United States
- 2School of Public Health and Health Sciences, University of Massachusetts – Amherst, Amherst, MA, United States
Introduction
There is increasing concern amongst public health professionals, environmental health scientists, and medical organizations about exposures to synthetic chemicals (Deborah Bennett et al., 2016; Bergman et al., 2013a; Di Renzo et al., 2015; Gore et al., 2015; Persson et al., 2022; Trasande et al., 2018) via polluted air and water, consumer products such as cosmetics, fabrics and upholstery, and food and packaging. These organizations’ concerns are based on the overwhelming evidence showing associations between chemical exposures and adverse health outcomes in human populations.
Some of the strongest evidence has come from persistent organic pollutants that bioaccumulate in the bodies of animals and people and bio magnify in the food chain. For example, per- and polyfluorinated alkyl substances, aka PFAS, have received significant attention following the C8 Health Project which was created after communities in Parkersburg, West Virginia (US) were affected by contamination of drinking water from the manufacturer of perfluorooctanoic acid (PFOA). People in these communities sued the manufacturer and, through a settlement agreement, medical monitoring of the population was developed (Frisbee Stephanie et al., 2009). The C8 Health Project and subsequent studies have revealed associations between PFOA exposures and human health effects including cardiometabolic issues, thyroid disorders, kidney and testicular cancer, and ulcerative colitis (Steenland et al., 2020).
Evidence accumulated over several decades also showed adverse effects associated with exposures to non-persistent chemicals including chemicals used in plastics, personal care products, solvents, detergents, food dyes, and pesticide ingredients (Zoeller et al., 2014; Skakkebaek et al., 2016; La Merrill et al., 2020; Vom Saal and Vandenberg, 2021; Matouskova and Vandenberg, 2022; Stacy et al., 2024). These chemicals are widely used in consumer products, and are so ubiquitous that they are considered pseudo-persistent, i.e., producing continuous exposures from external sources (Barceló and Petrovic, 2007). There are now thousands of studies showing associations between these chemicals and adverse health effects in humans including neurological disorders and learning disabilities, metabolic outcomes, infertility, thyroid dysfunction, and cancers (Bergman et al., 2013b; de Graaf et al., 2022; Gore et al., 2015; Hamed et al., 2023; Heindel et al., 2017; Miller et al., 2022; Muncke et al., 2020; Onyije et al., 2024; Patisaul, 2021; Rancière et al., 2015; Ribeiro et al., 2020; Wu et al., 2023; Zoeller et al., 2012).
The growing evidence linking chemical exposures to chronic diseases has led experts to deem the testing approaches recommended by regulatory agencies for risk assessment (EPA, 2023; FDA, 2000) insufficient to protect human health (Bergman et al., 2013a; Bennett et al., 2016; Anderko, 2017; Prins et al., 2019; Vandenberg, 2019; Vom Saal, 2019; Vandenberg, 2021b; Kassotis et al., 2022). Many endpoints such as developmental neurotoxicity, immunotoxicity, endocrine disruption and non-genotoxic carcinogenicity lack appropriate assays to protect human health. Testing that relies on more sensitive and health-relevant endpoints would reduce or eliminate exposures to hazardous chemicals before they enter the marketplace (Zimmermann et al., 2022).
In this commentary, we describe what better testing approaches for use in risk assessment would look like and how improvements in these tests would positively impact human health. We also discuss how inadequate risk management approaches lead to insufficient protections of human health. Although our focus is mostly on the United States, our conclusions are generally applicable to other countries.
What does better testing look like?
Although the exact number of chemicals remains unknown, scientists estimate there are 140,000–300,000 chemicals on the global market (Wang et al., 2020). In the US more than 42,000 chemicals listed on the US Environmental Protection Agency’s Toxic Substances Control Act (TSCA) inventory are currently in use in consumer products or in industrial processes. Furthermore, worldwide there are more than 12,000 chemicals authorized to use in the manufacturing of materials in contact with food (Groh et al., 2021) and the US Food and Drug Administration (FDA) has authorized more than 10,000 chemicals to be directly used in food or in food packaging and processing equipment (Neltner et al., 2011). The identity of many of these chemicals remains unknown because they are shielded as “confidential business information” or because they are registered in other countries without public disclosures (Vandenberg et al., 2023). One problem with the current approach to chemical testing in the US is that the data gaps for these chemicals are extensive. For instance, evaluations of ingredients added to food indicate that less than 25% have a feeding study that can be used to calculate safe levels of exposure and less than 10% have either reproductive or developmental toxicity data available (Neltner et al., 2013). Others have also reported on the lack of data for food ingredients (Faustman et al., 2021; Matouskova et al., 2023).
With the number of chemicals currently on the market, the problem is not only that we have failed to test a large number of them prior to their authorization, but that often the hazards of these chemicals are revealed years after they enter commerce, and in the US, there are very few options to restrict the use of chemicals once they have been allowed in products. With the exception of pesticide ingredients which are routinely reevaluated by the US EPA, chemicals used in food packaging, consumer products, and industrial processes do not undergo post-market re-evaluation, so even when studies reveal harmful effects of exposures to these chemicals, the options to restrict their uses are limited. This means that pre-market testing is critical to protect the health of humans and the environment.
To address these problems collectively, we need reliable assays that can be used for risk assessment and regulatory purposes (Cediel-Ulloa et al., 2022; Legler et al., 2020; Schug et al., 2013a; Schug et al., 2013b; Street et al., 2021; Vandenberg et al., 2019; Vandenberg, 2021a; b). It is not sufficient to develop in vitro screening tests like those identified as new approach methodologies (NAMs), it is also necessary to demonstrate that those NAMs are as good, if not better, than modern mammalian tests at identifying hazards (Kortenkamp et al., 2020; De Castelbajac et al., 2023; Tal et al., 2024). NAMs also need to go through validation processes to show that they are reproducible in other groups. Also, assays should accurately identify exposure levels where adverse effects do not occur. Lastly, regulators are expected to use data from assays, including NAMs, to protect the public’s health rather than protecting chemicals from further scrutiny. None of these has been done successfully to date.
Better testing would also use class-based approaches, like those that are required of the FDA but that have not been implemented (Maffini et al., 2023); with this approach, data from a few chemicals can be used to regulate others in the same class before they reach the market. As there is increasing evidence that chemicals in the food supply and in consumer products cause harm (Maffini and Vandenberg, 2017; Groh et al., 2019; Muncke, 2021), there needs to be evidence-based periodic post-market reevaluations and updated risk management decisions to remove the bad actors without introducing regrettable replacements (Woodruff et al., 2023).
Another issue is that many of the standard assays used to evaluate some hazards (often described in internationally-recognized test guidelines) focus on signs of acute toxicity rather than outcomes that are relevant to chronic diseases and conditions that are increasing in human populations (Lupu et al., 2020; Vandenberg, 2021a; b). For example, there are limited approaches to determine if chemicals affect the breast, even though there is increasing evidence that girls are experiencing premature breast development, increasing reports of shortened duration of breastfeeding in women that want to nurse, and increasing rates of premenopausal breast cancers (Kay et al., 2022). Although mammary glands are collected in some rodent toxicity tests, mammary gland development and function remains understudied in toxicity tests (Matouskova et al., 2022). To date, relatively few high-throughput in vitro approaches, including NAMs, have been developed that focus on chronic noncommunicable diseases, but this is critical considering these conditions are the most important challenges to the health of modern human populations (Groh and Muncke, 2017; Muncke et al., 2023).
Human studies finding associations between early life exposure to chemicals indicate that toxicity testing should focus on health-related outcomes rather than overt signs of toxicity. Examples of concerning early-life exposures from epidemiology studies are dichlorodiphenyltrichloroethane (DDT) and later life breast cancer risk (Cohn et al., 2015; Cohn et al., 2019), perchlorate and diminished IQ levels in children (Steinmaus et al., 2010; Brent, 2014; Taylor et al., 2014), and bisphenol A (BPA) and increased risk of asthma in children (Xie et al., 2016; Wu et al., 2021; Abellan et al., 2022). Good testing approaches should expand the endpoints to include human-health relevant outcomes. If this can be done within the context of NAMs, it will help to speed up the evaluation process, but many of these outcomes are complex and will be challenging to assess outside of whole animals.
Current hazard identification approaches continue to rely on outdated principles and expectations. For example, common testing approaches assume that chemicals are quickly eliminated from the body, something that many PFAS and other persistent organic pollutants have disproven, even considering species-specific differences in their half-lives (Olsen et al., 2007). In fact, this assumption continues to create problems in the testing (and risk management) of shorter-chain PFAS, which were assumed to be less bioaccumulative, and thus less hazardous, than the long-chain PFAS. Unfortunately, this was revealed to be untrue (Kabadi et al., 2018; Rice et al., 2020; Rice et al., 2023). Another long-held assumption is that chemical metabolites are less hazardous than the parent compounds. Phthalates, which have several metabolites that are more biologically active than the parent compounds, have disproven this assumption as well (Zhang et al., 2021).
Current approaches also rely on the assumption that testing chemicals one at a time is appropriate to understand how chemicals act under real-world conditions. Numerous mixture studies, including ones that demonstrated cumulative effects, have disproven this assumption (Christiansen et al., 2020; Martin et al., 2021; Caporale et al., 2022). For example, studies combining chemicals at concentrations that were 80-fold lower than their individual lowest-observed-adverse-effect-levels can act together to induce malformations of the male reproductive tract (Conley et al., 2018). Human mixture studies focused on real-world mixtures from human biomonitoring have revealed that some chemicals drive disease risk more than others (Escher et al., 2022; Luijten et al., 2023). Importantly, these chemicals are used in different kinds of products (e.g., consumer products, cosmetics, industrial products, food packaging) and thus are regulated very differently.
Lastly, testing on adult animals (or in cultured cells) has been assumed to predict effects on developing animals. Numerous examples of environmental chemicals including many endocrine disrupting chemicals have shown this to be false (Balbus et al., 2013; Grandjean et al., 2015; Heindel and Vandenberg, 2015; Treviño and Katz, 2018). Rather, significant evidence suggests that early life exposures to chemicals can have profound, unique, and lasting effects on individuals (Bourguignon et al., 2013; Di Pietro et al., 2023) and future generations (Sargis et al., 2019).
To address these challenges, long-held assumptions that have driven risk assessment and regulations for more than half a century should be complemented—if not completely replaced—with modern scientific principles of toxicology including mixture toxicology, endocrinology, physiology, and immunology (Vandenberg et al., 2013). Testing needs to be nimbler to account for the growth in knowledge of these fields over the last three decades and the new knowledge that is yet to come as well as the complexity of chemical exposures and new chemistries (Arthur et al., 2015a; Arthur et al., 2015b).
Improved testing leads to better risk management
The results of testing for hazard identification, like those described above, are used for risk assessment (Beronius et al., 2009). The National Academies (National Academies of Science, 1983) define risk assessment as “the use of the factual base to define the health effects of exposure of individuals or populations to hazardous materials and situations.” Risk assessment involves the combination of hazard, exposure, and dose response data to quantify the probability of an adverse effect at a specific level of exposure. After a risk assessment is performed, the next step is to decide whether the risk to health is substantial enough that it must be managed. Risk management is defined as “the process of weighing policy alternatives and selecting the most appropriate regulatory action, integrating the results of risk assessment with engineering data and with social, economic, and political concerns to reach a decision.”
Regulation is a common tool to manage risk. Regulations should allow chemicals to be used safely and appropriately through use limitations and restrictions. Regulations are bound by jurisdictional laws which means that the same chemical is regulated differently if it is used in toys than in food, even though the hazards remain the same. The legislative bodies writing these laws (e.g., at federal or state level in the US) are often slow to act, putting the public’s health at risk. But even when laws regulating chemicals are available, regulatory agencies then interpret and implement those laws through rules and regulations that can take broad or narrow approaches to protect the public. For example, chemical restrictions themselves can vary in severity, with bans as the most protective measure. A ban can include a total restriction in use of individual chemicals (methylene chloride in paint strippers (EPA, 2024); an entire class of chemicals (e.g., PFAS in food packaging (FDA, 2016; State, 2018); or groups of chemicals with similar adverse effects (e.g., anti-androgenic phthalates in children’s toys (Consumer Product Safety Commission, 2017). The least protective risk management is based on good manufacturing practice, which means that a chemical is permitted to be used at concentrations needed for the final article to perform properly, but no more (FDA, 1977). In general, the amounts that are actually used in the product are only known to the manufacturer. Other restrictions include specific migration limits (e.g., the amount of a chemical or mixture of chemicals that is allowed to be released from the product into food); restrictions that are focused on specific vulnerable populations (e.g., the restriction of a chemical in infant formula (FDA 2024a); consumption limits per day or per week that will not increase health risks (EFSA Panel on Food Contact Materials et al., 2023); and limits to the amount of a chemical added to the final article expressed by weight (FDA, 2005).
As stated above, risk assessment informs risk management (National Research Council, Division on Earth, Life Studies, Board on Environmental Studies, and Committee on Improving Risk Analysis Approaches Used by the US EPA, 2009) which may also consider economic cost to the regulated industry, availability of safer substitutes, societal values, political will and the precautionary principle. In an ideal world, risk assessment and risk management should be performed by different groups of experts (Maffini and Birnbaum, 2024) to ensure that the risk assessment is solely based on scientific evidence and is not influenced by the “costs” of taking action. This separation of risk assessment and risk management is certainly feasible, since this is the approach taken in the EU; for example, risk assessment for chemicals used in food and food packaging is conducted by the European Food Safety Authority whereas risk management decisions are the task of the European Commission. The subjective nature of risk management lends itself to criticism especially when it dismisses or disregards the risk assessment conclusions, and challenging a management decision usually causes delays in public health protection. Examples of delays include pesticides such as chlorpyrifos (Trasande, 2017) and glyphosate (Vandenberg et al., 2017), as well as chemicals in consumer products such as phthalates in food contact materials (Edwards, 2023) and building materials (asbestos) (Järvholm and Burdorf, 2024; Phillips, 2024). Unfortunately, risk management is often dependent on the strength of political will.
A role for civil society
When testing is insufficient to identify the most concerning hazards associated with a chemical, and risk management strategies fail to protect vulnerable populations from concerning exposures, the public is left to act. Commonly used tools include educational campaigns to move consumers away from products that have chemicals of concern (Defend Our Health, 2017). Another option is to submit petitions to the relevant agency arguing the there is strong evidence a chemical presents a high risk to health, the lack of a risk assessment or the use of the chemical not meeting the standard of safety (FDA 2024b). An example of this is a petition that require FDA to demonstrate the safety of long-chain PFAS in food packaging, which the agency responded to by removing approval of three types of long-chain PFAS (FDA, 2016). Members of civil society can also sue a regulatory agency for not implementing a protective law (Center for Food Safety, 2022) or product manufacturers when experts have assembled sufficient evidence, meeting a legal burden of proof, that a chemical causes serious harm. For example, repeated lawsuits against manufacturers of herbicides containing glyphosate have been successful because of strong evidence these products increase the risk of Non-Hodgkin’s Lymphoma (Zhang et al., 2019), even though the EPA maintains that glyphosate does not cause cancer (Benbrook, 2019).
These examples show that the public is a powerful force to push regulators and the regulated community to address problematic chemicals. The role of civil society is especially critical when risk management decisions lag for years or lack sufficient teeth to protect the public’s health. Similarly, citizens have been willing to take action when academic studies and epidemiology findings reveal harmful effects of chemicals, even if those outcomes are not evaluated in traditional test guidelines or accounted for in an agency’s risk assessment and risk management decisions.
Conclusion
We must be able to live with risk; nothing in our world is absent of risk. The problems we describe here illustrate a common paradox in US regulatory agencies: they are mandated to make safety decisions based on science that is constantly evolving while the risk management is commonly static. In other words, periodic reassessment of decisions based on new scientific evidence is not common in the US, with the exception of pesticides.
We argue that better testing will result in better risk assessments, and with better risk assessment, there is an opportunity for better risk management. Better testing, and better use of testing data, can protect the public’s health. However, this is not a given. Risk management involves numerous subjective factors including political will, which is often lacking.
Author contributions
MVM: Conceptualization, Writing–original draft, Writing–review and editing. LNV: Conceptualization, Writing–original draft, Writing–review and editing.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Publication costs were funded by an award from the Cornell Douglas Foundation (to LNV).
Acknowledgments
MM and LV did not receive compensation for this work.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Abellan, A., Mensink-Bout, S. M., Garcia-Esteban, R., Beneito, A., Chatzi, L., Duarte-Salles, T., et al. (2022). In utero exposure to bisphenols and asthma, wheeze, and lung function in school-age children: a prospective meta-analysis of 8 European birth cohorts. Environ. Int. 162, 107178. doi:10.1016/j.envint.2022.107178
Arthur, A. J., Karanewsky, D. S., Liu, H., Chi, B., and Markison, S. (2015a). Toxicological evaluation of the flavour ingredient 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carb oxylic acid. Toxicol. Rep. 2, 1255–1264. doi:10.1016/j.toxrep.2015.08.012
Arthur, A. J., Karanewsky, D. S., Luksic, M., Goodfellow, G., and Daniels, J. (2015b). Toxicological evaluation of two flavors with modifying properties: 3-((4-amino-2,2-dioxido-1h-benzo[c] [1,2,6]thiadiazin-5-yl)oxy)-2,2-dimethyl-n-pro pylpropanamide and (s)-1-(3-(((4-amino-2,2-dioxido-1h-benzo[c] [1,2,6]thiadiazin-5-yl)oxy)methyl)pipe ridin-1-yl)-3-methylbutan-1-one. Food Chem. Toxicol. 76, 33–45. doi:10.1016/j.fct.2014.11.018
Balbus, J. M., Barouki, R., Birnbaum, L. S., Etzel, R. A., Gluckman, P. D., Grandjean, P., et al. (2013). Early-life prevention of non-communicable diseases. Lancet 381, 3–4. doi:10.1016/S0140-6736(12)61609-2
Barceló, D., and Petrovic, M. (2007). Pharmaceuticals and personal care products (PPCPS) in the environment. Anal. Bioanal. Chem. 387, 1141–1142. doi:10.1007/s00216-006-1012-2
Benbrook, C. M. (2019). How did the US EPA and IARC reach diametrically opposed conclusions on the genotoxicity of glyphosate-based herbicides? Environ. Sci. Eur. 31, 2–16. doi:10.1186/s12302-018-0184-7
Bennett, D., Bellinger, D. C., Birnbaum, L. S., Bradman, A., Chen, A., Cory-Slechta, D. A., et al. (2016). Project TENDR: targeting environmental neuro-developmental risks the TENDR consensus statement. Environ. health Perspect. 124, A118–A122. doi:10.1289/EHP358
Bergman, A., Heindel, J., Jobling, S., Kidd, K., and Zoeller, R. (2013a). The state-of-the-science of endocrine disrupting chemicals – 2012. Available at: http://www.who.int/iris/bitstream/10665/78101/1/9789241505031_eng.pdf.
Bergman, Å., Heindel, J. J., Kasten, T., Kidd, K. A., Jobling, S., Neira, M., et al. (2013b). The impact of endocrine disruption: a consensus statement on the state of the science. Environ. Health Perspect. 121, a104–a106. doi:10.1289/ehp.1205448
Beronius, A., Ruden, C., Hanberg, A., and Hakansson, H. (2009). Health risk assessment procedures for endocrine disrupting compounds within different regulatory frameworks in the European Union. Regul. Toxicol. Pharmacol. 55, 111–122. doi:10.1016/j.yrtph.2009.05.019
Bourguignon, J. P., Franssen, D., Gérard, A., Janssen, S., Pinson, A., Naveau, E., et al. (2013). Early neuroendocrine disruption in hypothalamus and hippocampus: developmental effects including female sexual maturation and implications for endocrine disrupting chemical screening. J. Neuroendocrinol. 25, 1079–1087. doi:10.1111/jne.12107
Brent, G. A. (2014). Perchlorate exposure in pregnancy and cognitive outcomes in children: it's not your mother's thyroid. J. Clin. Endocrinol. Metabolism 99, 4066–4068. doi:10.1210/jc.2014-3673
Caporale, N., Leemans, M., Birgersson, L., Germain, P. L., Cheroni, C., Borbély, G., et al. (2022). From cohorts to molecules: adverse impacts of endocrine disrupting mixtures. Sci. (New York, NY) 375, eabe8244. doi:10.1126/science.abe8244
Cediel-Ulloa, A., Lupu, D. L., Johansson, Y., Hinojosa, M., Özel, F., and Rüegg, J. (2022). Impact of endocrine disrupting chemicals on neurodevelopment: the need for better testing strategies for endocrine disruption-induced developmental neurotoxicity. Expert Rev. Endocrinol. metabolism 17, 131–141. doi:10.1080/17446651.2022.2044788
Center for Food Safety (2022). Groups sue EPA over decades of inaction on harmful endocrine-disrupting pesticides.
Christiansen, S., Axelstad, M., Scholze, M., Johansson, H. K. L., Hass, U., Mandrup, K., et al. (2020). Grouping of endocrine disrupting chemicals for mixture risk assessment - evidence from a rat study. Environ. Int. 142, 105870. doi:10.1016/j.envint.2020.105870
Cohn, B. A., Cirillo, P. M., and Terry, M. B. (2019). DDT and breast cancer: prospective study of induction time and susceptibility windows. J. Natl. Cancer Inst. 111, 803–810. doi:10.1093/jnci/djy198
Cohn, B. A., La Merrill, M., Krigbaum, N. Y., Yeh, G., Park, J. S., Zimmermann, L., et al. (2015). DDT exposure in utero and breast cancer. J. Clin. Endocrinol. Metab. 100, 2865–2872. doi:10.1210/jc.2015-1841
Consumer Product Safety Commission (2017). Prohibition of children's toys and child care articles containing specified phthalates. Fed. Reg. 16 CFR 1307.
Conley, J. M., Lambright, C. S., Evans, N., Cardon, M., Furr, J., Wilson, V. S., et al. (2018). Mixed “antiandrogenic” chemicals at low individual doses produce reproductive tract malformations in the male rat. Toxicol. Sci. 164, 166–178. doi:10.1093/toxsci/kfy069
Defend Our Health (2017). Let’s kick chemicals out of our mac & cheese. Available at: https://defendourhealth.org/campaigns/safe-food/detox-mac-cheese/.
De Castelbajac, T., Aiello, K., Arenas, C. G., Svingen, T., Ramhøj, L., Zalko, D., et al. (2023). Innovative tools and methods for toxicity testing within PARC work package 5 on hazard assessment. Front. Toxicol. 5, 1216369. doi:10.3389/ftox.2023.1216369
de Graaf, L., Boulanger, M., Bureau, M., Bouvier, G., Meryet-Figuiere, M., Tual, S., et al. (2022). Occupational pesticide exposure, cancer and chronic neurological disorders: a systematic review of epidemiological studies in greenspace workers. Environ. Res. 203, 111822. doi:10.1016/j.envres.2021.111822
Di Pietro, G., Forcucci, F., and Chiarelli, F. (2023). Endocrine disruptor chemicals and children's health. Int. J. Mol. Sci. 24, 2671. doi:10.3390/ijms24032671
Di Renzo, G. C., Conry, J. A., Blake, J., DeFrancesco, M. S., DeNicola, N., Martin, J. N., et al. (2015). International Federation of Gynecology and Obstetrics opinion on reproductive health impacts of exposure to toxic environmental chemicals. Int. J. Gynaecol. Obstet. 131, 219–225. doi:10.1016/j.ijgo.2015.09.002
Edwards, R. G. (2023). FDA reaffirms it will not prohibit use of certain phthalates as food-contact substances. ArentFox Schiff. Available at: https://www.afslaw.com/perspectives/consumer-products-watch/fda-reaffirms-it-will-not-prohibit-use-certain-phthalates-food.
EFSA Panel on Food Contact Materials E, Aids, P., Lambré, C., Barat Baviera, J. M., Bolognesi, C., Chesson, A., et al. (2023). Re-evaluation of the risks to public health related to the presence of bisphenol a (BPA) in foodstuffs. EFSA J. 21, e06857. doi:10.2903/j.efsa.2023.6857
EPA (2023). Biden-Harris administration finalizes ban on most uses of methylene chloride, protecting workers and communities from fatal exposure. Available at: https://www.epa.gov/newsreleases/biden-harris-administration-finalizes-ban-most-uses-methylene-chloride-protecting.
EPA (2024). EDSP test guidelines and guidance document. Available at: https://www.epa.gov/test-guidelines-pesticides-and-toxic-substances/edsp-test-guidelines-and-guidance-document.
Escher, B. I., Lamoree, M., Antignac, J. P., Scholze, M., Herzler, M., Hamers, T., et al. (2022). Mixture risk assessment of complex real-life mixtures-the panoramix project. Int. J. Environ. Res. Public Health 19, 12990. doi:10.3390/ijerph192012990
Faustman, C., Aaron, D., Negowetti, N., and Leib, E. B. (2021). Ten years post-GAO assessment, FDA remains uninformed of potentially harmful GRAS substances in foods. Crit. Rev. Food Sci. Nutr. 61, 1260–1268. doi:10.1080/10408398.2020.1756217
FDA (1977). 21 Code of Federal Regulation Part 181. Available at: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-181.
FDA (2005). FDA threshold of regulation exemption. Available at: https://www.cfsanappsexternal.fda.gov/scripts/fdcc/index.cfm?set=TOR&id=2005-006.
FDA (2016). Indirect Food Additives: Paper and Paperboard Components. Fed. Reg. 21 CFR 176. Available at: https://www.federalregister.gov/documents/2016/01/04/2015-33026/indirect-food-additives-paper-and-paperboard-components.
FDA (2024a). FCN No. 2342. Asahi Kasei Corporation. Available at: https://www.cfsanappsexternal.fda.gov/scripts/fdcc/index.cfm?set=FCN&id=2342.
FDA (2024b). List of select chemicals in the food supply under FDA review. Available at: https://www.fda.gov/food/food-chemical-safety/list-select-chemicals-food-supply-under-fda-review.
Frisbee Stephanie, J., Brooks, A. P., Maher, A., Flensborg, P., Arnold, S., Fletcher, T., et al. (2009). The C8 Health project: design, methods, and participants. Environ. Health Perspect. 117, 1873–1882. doi:10.1289/ehp.0800379
Gore, A. C., Chappell, V. A., Fenton, S. E., Flaws, J. A., Nadal, A., Prins, G. S., et al. (2015). EDC-2: the Endocrine Society's second scientific statement on endocrine-disrupting chemicals. Endocr. Rev. 36, E1-E150–E150. doi:10.1210/er.2015-1010
Grandjean, P., Barouki, R., Bellinger, D. C., Casteleyn, L., Chadwick, L. H., Cordier, S., et al. (2015). Life-long implications of developmental exposure to environmental stressors: new perspectives. Endocrinology 156, 3408–3415. doi:10.1210/EN.2015-1350
Groh, K. J., Backhaus, T., Carney-Almroth, B., Geueke, B., Inostroza, P. A., Lennquist, A., et al. (2019). Overview of known plastic packaging-associated chemicals and their hazards. Sci. Total Environ. 651, 3253–3268. doi:10.1016/j.scitotenv.2018.10.015
Groh, K. J., Geueke, B., Martin, O., Maffini, M., and Muncke, J. (2021). Overview of intentionally used food contact chemicals and their hazards. Environ. Int. 150, 106225. doi:10.1016/j.envint.2020.106225
Groh, K. J., and Muncke, J. (2017). In vitro toxicity testing of food contact materials: state-of-the-art and future challenges. Compr. Rev. Food Sci. Food Saf. 16, 1123–1150. doi:10.1111/1541-4337.12280
Hamed, M. A., Akhigbe, T. M., Adeogun, A. E., Adesoye, O. B., and Akhigbe, R. E. (2023). Impact of organophosphate pesticides exposure on human semen parameters and testosterone: a systematic review and meta-analysis. Front. Endocrinol. 14, 1227836. doi:10.3389/fendo.2023.1227836
Heindel, J. J., Blumberg, B., Cave, M., Machtinger, R., Mantovani, A., Mendez, M. A., et al. (2017). Metabolism disrupting chemicals and metabolic disorders. Reprod. Toxicol. 68, 3–33. doi:10.1016/j.reprotox.2016.10.001
Heindel, J. J., and Vandenberg, L. N. (2015). Developmental origins of health and disease: a paradigm for understanding disease cause and prevention. Curr. Opin. Pediatr. 27, 248–253. doi:10.1097/MOP.0000000000000191
Järvholm, B., and Burdorf, A. (2024). Asbestos and disease–a public health success story? Scand. J. Work, Environ. Health 50, 53–60. doi:10.5271/sjweh.4146
Kabadi, S. V., Fisher, J., Aungst, J., and Rice, P. (2018). Internal exposure-based pharmacokinetic evaluation of potential for biopersistence of 6:2 fluorotelomer alcohol (FTOH) and its metabolites. Food Chem. Toxicol. 112, 375–382. doi:10.1016/j.fct.2018.01.012
Kassotis, C. D., Vom Saal, F. S., Babin, P. J., Lagadic-Gossmann, D., Le Mentec, H., Blumberg, B., et al. (2022). Obesity III: obesogen assays: limitations, strengths, and new directions. Biochem. Pharmacol. 199, 115014. doi:10.1016/j.bcp.2022.115014
Kay, J. E., Cardona, B., Rudel, R. A., Vandenberg, L. N., Soto, A. M., Christiansen, S., et al. (2022). Chemical effects on breast development, function, and cancer risk: existing knowledge and new opportunities. Curr. Environ. Health Rep. 9, 535–562. doi:10.1007/s40572-022-00376-2
Kortenkamp, A., Axelstad, M., Baig, A. H., Bergman, Å., Bornehag, C. G., Cenijn, P., et al. (2020). Removing critical gaps in chemical test methods by developing new assays for the identification of thyroid hormone system-disrupting chemicals-the athena project. Int. J. Mol. Sci. 21, 3123. doi:10.3390/ijms21093123
La Merrill, M. A., Vandenberg, L. N., Smith, M. T., Goodson, W., Browne, P., Patisaul, H. B., et al. (2020). Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat. Rev. Endocrinol. 16, 45–57. doi:10.1038/s41574-019-0273-8
Legler, J., Zalko, D., Jourdan, F., Jacobs, M., Fromenty, B., Balaguer, P., et al. (2020). The GOLIATH project: towards an internationally harmonised approach for testing metabolism disrupting compounds. Int. J. Mol. Sci. 21, 3480. doi:10.3390/ijms21103480
Luijten, M., Vlaanderen, J., Kortenkamp, A., Antignac, J. P., Barouki, R., Bil, W., et al. (2023). Mixture risk assessment and human biomonitoring: lessons learnt from HBM4EU. Int. J. Hyg. Environ. Health 249, 114135. doi:10.1016/j.ijheh.2023.114135
Lupu, D., Andersson, P., Bornehag, C. G., Demeneix, B., Fritsche, E., Gennings, C., et al. (2020). The ENDpoiNTs project: novel testing strategies for endocrine disruptors linked to developmental neurotoxicity. Int. J. Mol. Sci. 21, 3978. doi:10.3390/ijms21113978
Maffini, M. V., Rayasam, S. D., Axelrad, D. A., Birnbaum, L. S., Cooper, C., Franjevic, S., et al. (2023). Advancing the science on chemical classes. Environ. Health 21, 120. doi:10.1186/s12940-022-00919-y
Maffini, M. V., and Vandenberg, L. N. (2017). Closing the gap: improving additives safety evaluation to reflect human health concerns. Environ. Risk Assess. Remediat 1, 26–33. doi:10.4066/2529-8046.100028
Maffini, M. V., and Birnbaum, L. S. (2024). When it comes to food chemicals, Europe’s food safety agency and the FDA are oceans apart. Available at: https://www.ehn.org/fda-chemicals-in-food-2668083856.html.
Martin, O., Scholze, M., Ermler, S., McPhie, J., Bopp, S. K., Kienzler, A., et al. (2021). Ten years of research on synergisms and antagonisms in chemical mixtures: a systematic review and quantitative reappraisal of mixture studies. Environ. Int. 146, 106206. doi:10.1016/j.envint.2020.106206
Matouskova, K., Neltner, T. G., and Maffini, M. V. (2023). Out of balance: conflicts of interest persist in food chemicals determined to be generally recognized as safe. Environ. Health 22, 59. doi:10.1186/s12940-023-01004-8
Matouskova, K., Szabo, G. K., Daum, J., Fenton, S. E., Christiansen, S., Soto, A. M., et al. (2022). Best practices to quantify the impact of reproductive toxicants on development, function, and diseases of the rodent mammary gland. Reprod. Toxicol. 112, 51–67. doi:10.1016/j.reprotox.2022.06.011
Matouskova, K., and Vandenberg, L. N. (2022). “UV screening chemicals,” in Reproductive and developmental toxicology (Germany: Elsevier), 911–930.
Miller, M. D., Steinmaus, C., Golub, M. S., Castorina, R., Thilakartne, R., Bradman, A., et al. (2022). Potential impacts of synthetic food dyes on activity and attention in children: a review of the human and animal evidence. Environ. Health 21, 45. doi:10.1186/s12940-022-00849-9
Muncke, J. (2021). Tackling the toxics in plastics packaging. PLoS Biol. 19, e3000961. doi:10.1371/journal.pbio.3000961
Muncke, J., Andersson, A. M., Backhaus, T., Belcher, S. M., Boucher, J. M., Carney Almroth, B., et al. (2023). A vision for safer food contact materials: public health concerns as drivers for improved testing. Environ. Int. 180, 108161. doi:10.1016/j.envint.2023.108161
Muncke, J., Andersson, A. M., Backhaus, T., Boucher, J. M., Carney Almroth, B., Castillo Castillo, A., et al. (2020). Impacts of food contact chemicals on human health: a consensus statement. Environ. Health 19, 25. doi:10.1186/s12940-020-0572-5
National Academies of Science (1983). Risk assessment in the federal government: managing the process.
National Research Council, Division on Earth, Life Studies, Board on Environmental Studies, and Committee on Improving Risk Analysis Approaches Used by the US EPA (2009). Science and decisions: advancing risk assessment.
Neltner, T. G., Alger, H. M., Leonard, J. E., and Maffini, M. V. (2013). Data gaps in toxicity testing of chemicals allowed in food in the United States. Reprod. Toxicol. 42, 85–94. doi:10.1016/j.reprotox.2013.07.023
Neltner, T. G., Kulkarni, N. R., Alger, H. M., Maffini, M. V., Bongard, E. D., Fortin, N. D., et al. (2011). Navigating the US food additive regulatory program. Compr. Rev. Food Sci. Food Saf. 10, 342–368. doi:10.1111/j.1541-4337.2011.00166.x
Olsen, G. W., Burris, J. M., Ehresman, D. J., Froehlich, J. W., Seacat, A. M., Butenhoff, J. L., et al. (2007). Half-life of serum elimination of perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers. Environ. health Perspect. 115, 1298–1305. doi:10.1289/ehp.10009
Onyije, F. M., Dolatkhah, R., Olsson, A., Bouaoun, L., Deltour, I., Erdmann, F., et al. (2024). Risk factors for childhood brain tumours: a systematic review and meta-analysis of observational studies from 1976 to 2022. Cancer Epidemiol. 88, 102510. doi:10.1016/j.canep.2023.102510
Patisaul, H. B. (2021). Reproductive toxicology: endocrine disruption and reproductive disorders: impacts on sexually dimorphic neuroendocrine pathways. Reproduction 162, F111–F130. doi:10.1530/REP-20-0596
Persson, L., Carney Almroth, B. M., Collins, C. D., Cornell, S., de Wit, C. A., Diamond, M. L., et al. (2022). Outside the safe operating space of the planetary boundary for novel entities. Environ. Sci. Technol. 56, 1510–1521. doi:10.1021/acs.est.1c04158
Prins, G. S., Patisaul, H. B., Belcher, S. M., and Vandenberg, L. N. (2019). CLARITY-BPA academic laboratory studies identify consistent low-dose bisphenol a effects on multiple organ systems. Basic Clin. Pharmacol. Toxicol. 125 (Suppl. 3), 14–31. doi:10.1111/bcpt.13125
Rancière, F., Lyons, J. G., Loh, V. H., Botton, J., Galloway, T., Wang, T., et al. (2015). Bisphenol a and the risk of cardiometabolic disorders: a systematic review with meta-analysis of the epidemiological evidence. Environ. Health 14, 46. doi:10.1186/s12940-015-0036-5
Ribeiro, C. M., Beserra, B. T. S., Silva, N. G., Lima, C. L., Rocha, P. R. S., Coelho, M. S., et al. (2020). Exposure to endocrine-disrupting chemicals and anthropometric measures of obesity: a systematic review and meta-analysis. BMJ Open 10, e033509. doi:10.1136/bmjopen-2019-033509
Rice, P. A., Aungst, J., Cooper, J., Bandele, O., and Kabadi, S. V. (2020). Comparative analysis of the toxicological databases for 6:2 fluorotelomer alcohol (6:2 FTOH) and perfluorohexanoic acid (PFHXA). Food Chem. Toxicol. 138, 111210. doi:10.1016/j.fct.2020.111210
Rice, P. A., Kabadi, S. V., Doerge, D. R., Vanlandingham, M. M., Churchwell, M. I., Tryndyak, V. P., et al. (2023). Evaluating the toxicokinetics of some metabolites of a C6 polyfluorinated compound, 6:2 fluorotelomer alcohol in pregnant and nonpregnant rats after oral exposure to the parent compound. Food Chem. Toxicol. 183, 114333. doi:10.1016/j.fct.2023.114333
Sargis, R. M., Heindel, J. J., and Padmanabhan, V. (2019). Interventions to address environmental metabolism-disrupting chemicals: changing the narrative to empower action to restore metabolic health. Front. Endocrinol. 10, 33. doi:10.3389/fendo.2019.00033
Schug, T. T., Abagyan, R., Blumberg, B., Collins, T. J., Crews, D., DeFur, P. L., et al. (2013a). Designing endocrine disruption out of the next generation of chemicals. Green Chem. 15, 181–198. doi:10.1039/C2GC35055F
Schug, T. T., Heindel, J. J., Camacho, L., Delclos, K. B., Howard, P., Johnson, A. F., et al. (2013b). A new approach to synergize academic and guideline-compliant research: the CLARITY-BPA research program. Reprod. Toxicol. 40, 35–40. doi:10.1016/j.reprotox.2013.05.010
Skakkebaek, N. E., Rajpert-De Meyts, E., Buck Louis, G. M., Toppari, J., Andersson, A. M., Eisenberg, M. L., et al. (2016). Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol. Rev. 96, 55–97. doi:10.1152/physrev.00017.2015
Stacy, C., Amélie, C., Blanche, W., Audrey, R., Margaux, S., Simon, P., et al. (2024). A plausibility database summarizing the level of evidence regarding the hazards induced by the exposome on children health. Int. J. Hyg. Environ. Health 256, 114311. doi:10.1016/j.ijheh.2023.114311
State, W. (2018). Prohibition on the manufacture, sale, or distribution of certain food packaging—safer alternatives assessment by department of ecology—publication of findings—report to legislature—prohibition effective date contingent on findings. Fed Reg RCW 70A.222.070.
Steenland, K., Fletcher, T., Stein, C. R., Bartell, S. M., Darrow, L., Lopez-Espinosa, M.-J., et al. (2020). Review: evolution of evidence on PFOA and health following the assessments of the C8 Science Panel. Environ. Int. 145, 106125. doi:10.1016/j.envint.2020.106125
Steinmaus, C., Miller, M. D., and Smith, A. H. (2010). Perchlorate in drinking water during pregnancy and neonatal thyroid hormone levels in California. J. Occup. Environ. Med. 52, 1217–1224. doi:10.1097/JOM.0b013e3181fd6fa7
Street, M. E., Audouze, K., Legler, J., Sone, H., and Palanza, P. (2021). Endocrine disrupting chemicals: current understanding, new testing strategies and future research needs. Int. J. Mol. Sci. 22, 933. doi:10.3390/ijms22020933
Tal, T., Myhre, O., Fritsche, E., Rüegg, J., Craenen, K., Aiello-Holden, K., et al. (2024). New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project. Front. Toxicol. 6, 1359507. doi:10.3389/ftox.2024.1359507
Taylor, P. N., Okosieme, O. E., Murphy, R., Hales, C., Chiusano, E., Maina, A., et al. (2014). Maternal perchlorate levels in women with borderline thyroid function during pregnancy and the cognitive development of their offspring: data from the controlled antenatal thyroid study. J. Clin. Endocrinol. Metabolism 99, 4291–4298. doi:10.1210/jc.2014-1901
Trasande, L. (2017). When enough data are not enough to enact policy: the failure to ban chlorpyrifos. PLoS Biol. 15, e2003671. doi:10.1371/journal.pbio.2003671
Trasande, L., Shaffer, R. M., and Sathyanarayana, S.COUNCIL ON ENVIRONMENTAL HEALTH (2018). Food additives and child health. Pediatrics 142, e20181408. doi:10.1542/peds.2018-1408
Treviño, L. S., and Katz, T. A. (2018). Endocrine disruptors and developmental origins of nonalcoholic fatty liver disease. Endocrinology 159, 20–31. doi:10.1210/en.2017-00887
Vandenberg, L. N. (2019). Low dose effects challenge the evaluation of endocrine disrupting chemicals. Trends food Sci. Technol. 84, 58–61. doi:10.1016/j.tifs.2018.11.029
Vandenberg, L. N. (2021a). Endocrine disrupting chemicals: strategies to protect present and future generations. Expert Rev. Endocrinol. Metab. 16, 135–146. doi:10.1080/17446651.2021.1917991
Vandenberg, L. N. (2021b). Toxicity testing and endocrine disrupting chemicals. Adv. Pharmacol. 92, 35–71. doi:10.1016/bs.apha.2021.05.001
Vandenberg, L. N., Blumberg, B., Antoniou, M. N., Benbrook, C. M., Carroll, L., Colborn, T., et al. (2017). Is it time to reassess current safety standards for glyphosate-based herbicides? J. Epidemiol. Community Health 71, 613–618. doi:10.1136/jech-2016-208463
Vandenberg, L. N., Colborn, T., Hayes, T. B., Heindel, J. J., Jacobs, D. R., Lee, D. H., et al. (2013). Regulatory decisions on endocrine disrupting chemicals should be based on the principles of endocrinology. Reprod. Toxicol. 38, 1–15. doi:10.1016/j.reprotox.2013.02.002
Vandenberg, L. N., Hunt, P. A., and Gore, A. C. (2019). Endocrine disruptors and the future of toxicology testing - lessons from CLARITY-BPA. Nat. Rev. Endocrinol. 15, 366–374. doi:10.1038/s41574-019-0173-y
Vandenberg, L. N., Rayasam, S. D. G., Axelrad, D. A., Bennett, D. H., Brown, P., Carignan, C. C., et al. (2023). Addressing systemic problems with exposure assessments to protect the public's health. Environ. Health 21, 121. doi:10.1186/s12940-022-00917-0
Vom Saal, F. S. (2019). Flaws in design, execution and interpretation limit CLARITY-BPA's value for risk assessments of bisphenol a. Basic & Clin. Pharmacol. Toxicol. 125 (Suppl. 3), 32–43. doi:10.1111/bcpt.13195
Vom Saal, F. S., and Vandenberg, L. N. (2021). Update on the health effects of bisphenol a: overwhelming evidence of harm. Endocrinology 162, bqaa171. doi:10.1210/endocr/bqaa171
Wang, Z., Walker, G. W., Muir, D. C., and Nagatani-Yoshida, K. (2020). Toward a global understanding of chemical pollution: a first comprehensive analysis of national and regional chemical inventories. Environ. Sci. Technol. 54, 2575–2584. doi:10.1021/acs.est.9b06379
Woodruff, T. J., Rayasam, S. D. G., Axelrad, D. A., Koman, P. D., Chartres, N., Bennett, D. H., et al. (2023). A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement. Environ. Health 21, 132. doi:10.1186/s12940-022-00930-3
Wu, M., Wang, S., Weng, Q., Chen, H., Shen, J., Li, Z., et al. (2021). Prenatal and postnatal exposure to bisphenol a and asthma: a systemic review and meta-analysis. J. Thorac. Dis. 13, 1684–1696. doi:10.21037/jtd-20-1550
Wu, Q., Li, G., Zhao, C. Y., Na, X. L., and Zhang, Y. B. (2023). Association between phthalate exposure and obesity risk: a meta-analysis of observational studies. Environ. Toxicol. Pharmacol. 102, 104240. doi:10.1016/j.etap.2023.104240
Xie, M.-Y., Ni, H., Zhao, D.-S., Wen, L.-Y., Li, K.-S., Yang, H.-H., et al. (2016). Exposure to bisphenol a and the development of asthma: a systematic review of cohort studies. Reprod. Toxicol. 65, 224–229. doi:10.1016/j.reprotox.2016.08.007
Zhang, L., Rana, I., Shaffer, R. M., Taioli, E., and Sheppard, L. (2019). Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: a meta-analysis and supporting evidence. Mutat. Research/Reviews Mutat. Res. 781, 186–206. doi:10.1016/j.mrrev.2019.02.001
Zhang, Y.-J., Guo, J.-L., Xue, J.-c., Bai, C.-L., and Guo, Y. (2021). Phthalate metabolites: characterization, toxicities, global distribution, and exposure assessment. Environ. Pollut. 291, 118106. doi:10.1016/j.envpol.2021.118106
Zimmermann, L., Scheringer, M., Geueke, B., Boucher, J. M., Parkinson, L. V., Groh, K. J., et al. (2022). Implementing the EU chemicals strategy for sustainability: the case of food contact chemicals of concern. J. Hazard Mater 437, 129167. doi:10.1016/j.jhazmat.2022.129167
Zoeller, R. T., Bergman, Å., Becher, G., Bjerregaard, P., Bornman, R., Brandt, I., et al. (2014). A path forward in the debate over health impacts of endocrine disrupting chemicals. Environ. Health 13, 118. doi:10.1186/1476-069X-13-118
Keywords: US Food and Drug Administration, US Environmental Protection Agency, hazard assessment, per-and polyfluorinated alkyl substances, regulation
Citation: Maffini MV and Vandenberg LN (2024) Science evolves but outdated testing and static risk management in the US delay protection to human health. Front. Toxicol. 6:1444024. doi: 10.3389/ftox.2024.1444024
Received: 04 June 2024; Accepted: 23 July 2024;
Published: 13 August 2024.
Edited by:
Jan Willem Van Der Laan, Medicines Evaluation Board, NetherlandsReviewed by:
Hubert Dirven, Norwegian Institute of Public Health (NIPH), NorwayJyotigna Mehta, ADAMA Agricultural Solutions Ltd., United Kingdom
Copyright © 2024 Maffini and Vandenberg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Maricel V. Maffini, drmvma@gmail.com